Propiram, or N-(1-methyl-2-piperidinoethyl)-N-2-pyridylpropionamide, is a known oral analgesic which has opiate agonist-antagonist properties. It is generally employed in the form of its fumarate salt, which has the structural formula ##STR1##
Propiram acts primarily on the central nervous system. Orally, propiram fumarate has been found to be approximately one-twelfth as potent as intramuscular morphine (Saldana, L. R., Curr. Ther. Res. 28: 646-649, Nov. 1980) and 1/200 as active as the antagonist morphine. Jasinski (Br. J. Clin. Pharmacol. 7: 287A-90S, 1979, supplement) has reported that propiram fumarate seems to have less abuse potential than codeine or propoxyphene. Animal studies have revealed that the analgesic activity is comparable, in terms of effect and duration, to meperidine and codeine. The drug is regarded as less addicting than codeine and as causing less respiratory depression than codeine; it is generally administered orally, in 25 to 50 mg doses, every 4 hours for severe pain, not to exceed 300 mg daily. The most frequently encountered side effect appears to be drowsiness, with nausea, dizziness and psychomimetic effects occurring to a much lesser extent. See also The Merck Index, ninth edition, Merck & Co., Inc., Rahway, N.J. (1976), pp. 1014-1015 and the references cited therein.
Ibuprofen, or (.+-.)2-(p-isobutylphenyl)propionic acid, has the structural formula ##STR2## The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity; it is peripherally acting and inhibits prostaglandin synthesis. Ibuprofen is currently marketed in the United States as Motrin.RTM., which is available in 300, 400 and 600 mg tablets for oral administration. For the treatment of mild to moderate pain, 400 mg every 4 to 6 hours, not to exceed 2400 mg total daily dose, is generally recommended. See also Physicians' Desk Reference, 35th edition, 1981, pp. 1831-1833.
Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1Hpurine-2,6-dione, has the structural formula ##STR3## This substance has been used alone, intravenously, in the treatment of headaches and has also been used in combination with selected drugs. Compositions containing one or more of the analgesics aspirin, acetaminophen and phenacetin in combination with varying amounts of caffeine have been marketed in the past; in several cases, such non-narcotic analgesic/caffeine combination products have further included one of the narcotic analgesics codeine, propoxyphene or oxycodone. Examples of these combinations include the products known commercially as Excedrin.RTM., SK-65.RTM. Compound, Darvon.RTM. Compound, Anacin.RTM., A.P.C., and A.P.C. with Codeine, Tabloid.RTM. Brand. The nonsteroidal analgesic components of these mixtures have the following structural formulas: ##STR4##
The three narcotic analgesics which have occasionally been added to the aspirin/phenacetin/acetaminophen/caffeine combinations have the following structural formulas: ##STR5## As far as the present inventors know, however, the art has never suggested that caffeine be added to a narcotic analgesic to contribute to its analgesic effect.
Many workers have sought to demonstrate the efficacy of the aspirin/phenacetin/acetaminophen/caffeine combination products. An extensive review of the literature on caffeine and analgesics has been published ["Over-The-Counter Drugs: Establishment of a Monograph for OTC Internal Analgesic, Antipyretic and Antirheumatic Products," Federal Register, 1977, 42 (131): 35482-35485] and several relevant additional articles have appeared. Most animal studies on caffeine analgesia have been performed on the rat. Williams (Toxicology and Applied Pharmacology, 1959, 1:447-453) utilized experimental pain and found that caffeine alone exerted analgesic effects on rats and when combined with aspirin, the effect appeared additive but not potentiating. Vinegar et al (Proceedings of the Society for Experimental Biology and Medicine, 1976, 151:556-560), ten years later, found that in the rat caffeine potentiates the acute anti-inflammatory and analgesic activity of aspirin. Siegers (Pharmacology, 1973, 10:19-27) studied the effect of oral doses of caffeine (10, 50 and 100 mg/kg) given to rats together with acetaminophen and found that caffeine inhibited its absorption and lowered its serum concentration. He suggested that delayed stomach emptying as a result of the relaxing effect of caffeine on gastric smooth muscle was probably the cause of the diminished absorption of orally administered drugs in the presence of caffeine. Despite this finding, acetaminophen analgesia was not decreased by caffeine. In agreement with Williams and Vinegar and his associates, Siegers found that caffeine itself had analgesic activity. Only in the lowest dose of caffeine studied, a dose at which analgesia was not exhibited, was there a reduction in the acetaminophen induced analgesia. In a more recent paper, Seegers et al (Arch. Int. Pharmacodyn., 1981, 251:237-254) demonstrated an anti-inflammatory, analgesic effect of caffeine in rats. He also found that the combination of caffeine, aspirin and acetaminophen as well as the combination of caffeine, aspirin and phenacetin at low doses produced anti-inflammatory, analgesic effects which are at least as great as would be expected on the basis of addition, while at high doses, the results suggested potentiation. Citing the work of Giertz and Jurna (Naturwissenschaften, 1957, 44:445) and Fuchs and Giertz (Arzneimittelforsch, 1960, 10:526-530), who observed that caffeine induced analgesia in assays in mice in which inflammation was not involved, Seegers asserted that, "it seems safe to assume that the analgesic activity of caffeine consists of at least two components, one independent of and another one dependent on its anti-inflammatory activity."
The earliest relevant study in humans was reported by Wallenstein (Proceedings of the aspirin symposium, held at the Royal College of Surgeons, London, 1975). Two tablets of a combination in which each tablet contained aspirin 210 mg, acetaminophen 150 mg and caffeine 30 mg, clearly and significantly produced more analgesia than the combination without caffeine. The one tablet dose of the combination had higher mean scores than either component alone, but was not superior to the combination without caffeine. Wallenstein speculated that, "dosage may be an important factor, and caffeine may simply be ineffective much below the 60 mg dose". Booy (Nederlands Tijdschrift Voor Tandheelkinde, 1972, 79: 69-75) studied pain relief on each of two days after tooth extraction. Patients who reported "great pain" on the first day obtained more pain relief from 1000 mg of acetaminophen plus 100 mg of caffiene than from 1000 mg of acetaminophen alone. On the second day this difference was not found, although on both days all treatments were superior to placebo. Lim et al (Clin. Pharmacol. Ther., 1967, 8: 521-542) reporting a study in which experimental pain was induced in the subjects by bradykinin, observed that the combination of aspirin 520 mg and acetaminophen 260 mg given orally could not be distinguished from placebo, whereas the same combination in lesser quantities, aspirin 325 mg and acetaminophen 162.5 mg plus caffeine 32.5 mg was significantly different from placebo at 15, 60, 75, 105 and 120 minutes after taking the drug. A double-blind, crossover study of 216 patients by Wojcicki et al [Archivum Immunologiae et Therapeae Experimentalis, 1977, 25(2): 175-179] compared the activity of 1000 mg of acetaminophen plus 100 mg of caffeine against the same quantity of acetaminophen alone. One group of patients in the trial were suffering severe and frequently occurring idiopathic headache and a second group had moderate post-operative orthopedic pain. The authors concluded that the relief of pain was far greater with the caffeine combination than with acetaminophen alone or with aspirin alone. Jain et al (Clin. Pharmacol. Ther., 1978, 24: 69-75) first studied 70 postpartum patients with moderate to severe uterine cramp and/or episiotomy pain and then a second group of 70 patients limited to severe pain only. Comparing 800 mg aspirin plus 65 mg of caffeine to 650 mg of aspirin alone, these authors concluded that in patients with severe episiotomy pain the combination is the more effective analgesic.
Caffeine use in the treatment of headache has a long history. The FDA Advisory Panel, in its review of caffeine [Federal Register, 1977, 42(131): 35482-35485] argued that the known biochemical effect of caffeine on small blood vessels provides a plausible explanation for its effectiveness in treating headache associated with cerebral blood vessels. Recently Sechzer [Curr. Therapy Research, 1979, 26(4)] found that the intravenous administration of caffeine sodium benzoate rapidly provided relief in the majority of patients experiencing headache resulting from dural puncture or spinal anesthesia. The author, referring to the literature on the mechanism of action of caffeine on cerebral blood flow and on cerebral vascular tone, argues from the opposite perspective of the Panel that the analgesic relief obtained implies that an intracranial vascular component is the primary factory in such headaches.
Changes in mood and over all sense of "well being" after administration of caffeine have been widely reported in the literature. Beginning in the early part of this century, Hollingsworth (Arch. Psychol., 1912, 22: 1) reported beneficial motor and mental effects from 65 to 130 mg of caffeine, and tremor, poor motor performance, and insomnia caused by 390 mg of caffeine. Many studies over the past 70 years have confirmed these findings. Review articles on the xanthines [Ritchie, J. M., "Central nervous system stimulants. 2. The xanthines," Goodman, L. S. & Gilman, A. (Eds.) The pharmacological basis of therapeutics, 4th Ed., New York: Macmillian Co., 1970; Stephenson, P. E., "Physiologic and psychotropic effects of caffeine on man," J. Amer. Diet. Assoc., 1977, 71(3): 240-247] report that doses of 50 to 200 mg of caffeine result in increased alertness, decreased drowsiness, and lessened fatigue. Doses in the range of 200 to 500 mg may produce headaches, tremor, nervousness and irritability.
After extensively reviewing the relevant literature, the most significant contributions of which are summarized above, the FDA Advisory Panel in 1977 concluded that caffeine when used as an analgesic adjuvant was safe, but that there was insufficient data to demonstrate that caffeine contributes anything to the action of the analgesic [Federal Register, 1977, 42(131): 35482-35485]. The Panel stated:
Unfortunately, the information and data submitted, fail to demonstrate conclusively that caffeine in combination is effective as an analgesic, antipyretic and/or antirheumatic ingredient. The Panel finds there is little evidence to show that this ingredient even contributes to these pharmacological effects in the clinical situation.
This remains the official position on the question up to the present time. Consequently, many of the analgesic/caffeine combination products previously available are no longer on the market.
In addition to the few prior art instances of selected non-narcotic analgesic/caffeine combinations further containing a selected narcotic analgesic (which three-component combinations have already been discussed hereinabove), there also are examples in the art of two-component combinations of selected non-narcotic analgesics with selected narcotic analgesics. Known combinations of this type include Darvon.RTM. with A.S.A..RTM. (propoxyphene hydrochloride and aspirin), Darvon-N.RTM. with A.S.A..RTM. (propoxyphene napsylate and aspirin), aspirin with codeine, Talwin.RTM. Compound (pentazocine hydrochloride and aspirin), Percodan.RTM. (oxycodone hydrochloride, oxycodone terephthalate and aspirin) and nalbuphine with acetaminophen, the last-mentioned combination being disclosed in U.S. Pat. No. 4,237,140. The general principle of use of a combination of drugs to produce additive analgesic effects is known to those skilled in the art; for example, Foley et al, The Management of Cancer Pain, Volume II-The Rational Use of Analgesics in the Management of Cancer Pain, Hoffman-LaRoche Inc., 1981, suggest such combination and specifically point out that 650 mg aspirin of acetaminophen regularly added to the standard narcotic dose will often enhance the analgesic effect without requiring higher doses of the narcotic. Such additive effects have been reported earlier by Houde et al, Clin. Pharm. Ther. 1(2): 163-174 (1960) for intramuscularly administered morphine sulfate given with orally administered aspirin. As far as the present inventors know, however, the art does not suggest any two-component compositions of a narcotic analgesic and caffeine; it also does not suggest any improvements in the analgesic response to be derived from co-administering caffeine with any narcotic analgesic.